Table 3.

Selected Disorders of Interest in the Differential Diagnosis of PPP2R1A-Related Neurodevelopmental Disorder

GeneDiffDx DisorderMOIFeatures Observed in DiffDx Disorder & PPP2R1A-NDDDistinguishing Features
AKT3 MPPH syndrome 2ADMegalencephaly, epilepsy, hypotoniaPolydactyly, hydrocephalus, polymicrogyria in MPPH2
CCND2 MPPH syndrome 3ADMegalencephaly, epilepsyPolydactyly, hydrocephalus, polymicrogyria in MPPH3
EZH2 Weaver syndrome (See EZH2-Related Overgrowth.)ADMacrocephaly, seizures, frontal bossing, long face, ventriculomegaly, behavioral difficulties↑ prenatal/postnatal length, advanced bone age, & umbilical hernias are common in persons w/Weaver syndrome.
NSD1 Sotos syndrome ADMacrocephaly, neonatal hypotonia, large head, corpus callosum hypoplasia, large ventricles↑ prenatal/postnatal length & advanced bone age are common in persons w/Sotos syndrome.
PIK3CA MCAP syndrome (See PIK3CA-Related Overgrowth Spectrum.)See footnote 1.Megalencephaly, ventriculomegaly, hypotoniaPolymicrogyria, polydactyly in MCAP syndrome
PIK3R2 MPPH syndrome 1ADMegalencephaly, epilepsyPolydactyly, polymicrogyria in MPPH1
PPP2CA PPP2CA-related NDD (OMIM 618354)ADHypotonia, delayed walking & speech, Macro-/microcephaly, corpus callosum hypoplasia, enlarged ventriclesNone
PPP2R5D PPP2R5D-related NDD ADHypotonia, macrocephaly, frontal bossing, elongated face, large ventriclesCorpus callosum aplasia is more common in PPP2R1A-NDD.
RAC1 RAC1-related ID (OMIM 617751)ADMacro-/microcephaly, dysplastic ears, moderate-to-severe DD, seizures, enlarged ventriclesPossibly different facial dysmorphology, but otherwise none
TRIO TRIO-related ID ADMacro-/microcephaly, ID, behavioral manifestations, scoliosisHand & foot skeletal abnormalities in TRIO-ID

AD = autosomal dominant; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MCAP = megalencephaly-capillary malformation; MOI = mode of inheritance; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus; NDD = neurodevelopmental disorder


MCAP syndrome is not known to be inherited, as most identified pathogenic variants are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date.

From: PPP2R1A-Related Neurodevelopmental Disorder

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